Nell-1, A Cbfa 1 Downstream Target, In Bone Formation

Nell-1，Cbfa 1 下游目标，在骨形成中

基本信息

批准号：
7839166
负责人：
KANG TING
金额：
$ 40.07万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7839166
关键词：
Address Animals Antibodies Applications Grants Bacteriophage T7 Bacteriophages Binding Binding Proteins Binding Sites Biological Assay Bone Growth Bone Regeneration Cells Cephalic Chondrocytes Clinical Co-Immunoprecipitations Commit Craniosynostosis Cysteine-Rich Domain Data Development Down-Regulation Epidermal Growth Factor Family Financial compensation Foundations Funding Genetic Transcription Goals Hour Human Human Resources Hypertrophy In Vitro Infant Integrin Binding Integrins Investigation Joint structure of suture of skull Ligands Mass Spectrum Analysis Membrane Proteins Molecular N Domain N-terminal Natural regeneration Osteoblasts Osteogenesis Parents Patients Peptide Signal Sequences Phage Display Progress Reports Protein Isoforms Proteins Proteomics Public Health Recovery Regulation Resolution Resources Response Elements Surgical sutures System Techniques Testing Therapeutic Thrombospondin 1 Time Tissues Transcript Transcriptional Regulation United States National Institutes of Health Up-Regulation Work abstracting acute myeloid leukemia 1 protein base bone cDNA Library chordin cis acting element in vivo novel osteoblast differentiation osteochondral tissue osteogenic parent grant preclinical study premature promoter public health relevance receptor receptor binding relating to nervous system response secretory protein selective expression

项目摘要

DESCRIPTION (provided by applicant): Project Summery/Abstract This Competitive Revision Application is in response to Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. We previously identified osteoinductive molecule, long Nell-1 [LNell-1; a protein strongly expressed in neural tissue encoding epidermal growth factor (EGF)-like domain] from prematurely fusing sutures in craniosynostosis (CS) patients (Many of these studies were performed before identification of the short Nell-1, SNell-1 isoform. For clarification, we will use "LNell-1" in place of Nell-1 when we are certain that the long form is involved. Meanwhile, Nell-1 can refer to both LNell-1 and SNell-1). LNell-1 is a secretory protein with a signal peptide, an NH2-terminal thrombospondin-1 (TSP1-N)-like module, five chordin-like cysteine-rich (CR) domains, and EGF-like domains. The long term goal of this Competitive Revision and parent grant proposal is to understand the mechanisms behind excessive bone growth in CS patients, so that we can harness and channel the molecules responsible into clinical therapies to regenerate bone. Towards this end, we have worked continuously to better understand the molecular regulation and function of LNell-1 so as to build a strong scientific foundation for therapeutic LNell-1 application. Our progress report and preliminary data for the parent grant Competitive Renewal demonstrate that: 1) runt-related transcription factor 2 (Runx2) regulates LNell-1 through cis-acting element 2 (OSE2) response elements (REs); 2) LNell-1 increases osteoblastic differentiation and can partially compensate for Runx2 haploinsufficiency; and 3) Nell-1 deletion animals demonstrate impaired chondrocyte hypertrophy with delayed bone formation as well as decreased Runx2 and increased osterix expression. For this one-year Competitive Revision we propose to significantly accelerate the tempo of our current investigations on mechanistic regulation of Nell-1 by a concentrated focus on identification of LNell-1 receptors and/or binding proteins (R/BPs). To accomplish this objective, we have obtained preliminary T7 phage display and mass spectrometry (MS)-based proteomic data demonstrating LNell-1 binding to membranous and cytosolic proteins. These data have led to the hypothesis that Nell-1 exerts its function in osteochondral differentiation by serving as a ligand to cell specific and potentially novel receptors/binding proteins. In order to identify LNell-1 R/BPs, three aims representing a logical extension of the parent proposal will be undertaken: Aim A) Candidate receptor approach to examine interaction of LNell-1 with integrin family. Structurally, the TSP1-N-like domain of LNell-1 shares a high degree of similarity with TSP1-N domain where integrin binding sites reside. Aim B) LNell-1 R/BP identification using a T7 phage display system. Aim C) MS-based functional proteomics on the membranous protein fraction binding. This Competitive Revision will also stimulate the economy by enabling hiring of additional staff and increasing hours of current part-time staff. PUBLIC HEALTH RELEVANCE: RELEVANCE TO PUBLIC HEALTH STATEMENT Nell-1, a cause of excessive bone growth in craniosynostosis patients has shown significant promise as a potent bone forming agent in preclinical studies. A better understanding of how and why Nell-1 works to form bone can accelerate the development of clinical therapies to help patients grow better and faster bone.

描述（由申请人提供）：项目摘要/摘要此竞争性修订申请是为了响应通知编号 (NOT-OD-09-058) 和通知标题：NIH 宣布恢复法案资金可用于竞争性修订申请。我们之前鉴定出骨诱导分子，长Nell-1 [LNell-1;一种在编码表皮生长因子 (EGF) 样结构域的神经组织中强烈表达的蛋白质]，来自颅缝早闭 (CS) 患者缝线的过早融合（其中许多研究是在鉴定短 Nell-1、SNell-1 亚型之前进行的。澄清一下，当我们确定涉及长形式时，我们将使用“LNell-1”代替Nell-1，同时，Nell-1可以指代LNell-1和LNell-1。 SNell-1）。 LNell-1 是一种分泌蛋白，具有信号肽、NH2 末端血小板反应蛋白-1 (TSP1-N) 样模块、五个弦蛋白样富含半胱氨酸 (CR) 结构域和 EGF 样结构域。本竞争性修订和家长资助提案的长期目标是了解 CS 患者骨骼过度生长背后的机制，以便我们能够利用和引导负责的分子进入临床治疗以再生骨骼。为此，我们不断致力于更好地了解LNell-1的分子调控和功能，为LNell-1的治疗应用奠定坚实的科学基础。我们的进展报告和母基金竞争性更新的初步数据表明：1）runt相关转录因子2（Runx2）通过顺式作用元件2（OSE2）反应元件（RE）调节LNell-1； 2）LNell-1增加成骨细胞分化，可以部分补偿Runx2单倍体不足； 3) Nell-1 缺失动物表现出软骨细胞肥大受损、骨形成延迟以及 Runx2 减少和 osterix 表达增加。在为期一年的竞争性修订中，我们建议通过集中鉴定 LNell-1 受体和/或结合蛋白 (R/BP) 来显着加快目前对 Nell-1 机制调控的研究节奏。为了实现这一目标，我们获得了初步的 T7 噬菌体展示和基于质谱 (MS) 的蛋白质组数据，证明 LNell-1 与膜和胞浆蛋白结合。这些数据得出这样的假设：Nell-1 通过充当细胞特异性和潜在新型受体/结合蛋白的配体来发挥其在骨软骨分化中的功能。为了识别 LNell-1 R/BP，将实现代表母提案的逻辑扩展的三个目标：目标 A) 候选受体方法来检查 LNell-1 与整联蛋白家族的相互作用。在结构上，LNell-1 的 TSP1-N 样结构域与整合素结合位点所在的 TSP1-N 结构域具有高度相似性。目标 B) 使用 T7 噬菌体展示系统鉴定 LNell-1 R/BP。目标 C) 基于 MS 的膜蛋白组分结合功能蛋白质组学。此次竞争性修订还将通过雇用更多员工和增加现有兼职员工的工作时间来刺激经济。公共卫生相关性：与公共卫生声明的相关性 Nell-1 是颅缝早闭患者骨质过度生长的原因之一，在临床前研究中显示出作为有效的成骨剂的巨大前景。更好地了解 Nell-1 如何以及为何形成骨骼可以加速临床疗法的开发，帮助患者更好更快地生长骨骼。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preparation and characterization of trace elements-multidoped injectable biomimetic materials for minimally invasive treatment of osteoporotic bone trauma.

DOI：
10.1002/jbm.a.32936
发表时间：
2010-12
期刊：
Journal of biomedical materials research. Part A
影响因子：
0
作者：
Xianyan Yang;Yilai Gan;Xin Gao;Li Zhao;Changyou Gao;Xinli Zhang;Yanbo Feng;K. Ting;Z. Gou
通讯作者：
Xianyan Yang;Yilai Gan;Xin Gao;Li Zhao;Changyou Gao;Xinli Zhang;Yanbo Feng;K. Ting;Z. Gou

The use of BMP-2 coupled - Nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects.

DOI：
10.1016/j.biomaterials.2010.08.041
发表时间：
2010-12
期刊：
BIOMATERIALS
影响因子：
14
作者：
Zheng, Zhong;Yin, Wei;Zara, Janette N.;Li, Weiming;Kwak, Jinny;Mamidi, Rachna;Lee, Min;Siu, Ronald K.;Ngo, Richard;Wang, Joyce;Carpenter, Doug;Zhang, Xinli;Wu, Benjamin;Ting, Kang;Soo, Chia
通讯作者：
Soo, Chia

A new function of Nell-1 protein in repressing adipogenic differentiation.

DOI：
10.1016/j.bbrc.2011.06.111
发表时间：
2011-07-22
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
James, Aaron W.;Pan, Angel;Chiang, Michael;Zara, Janette N.;Zhang, Xinli;Ting, Kang;Soo, Chia
通讯作者：
Soo, Chia

NELL-1 binds to APR3 affecting human osteoblast proliferation and differentiation.